CK2-dependent Degradation of CBX3 Dictates Replication Fork Stalling and PARP Inhibitor Sensitivity

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 May 23

PMID 38781342

Authors

Jian Ma

Dianyun Ren

Zixi Wang

Wei Li

Tianjie Liu

Qi Ye

Yuzeshi Lei

Yanlin Jian

Bohan Ma

Yizeng Fan

Jing Liu

Yang Gao

Xin Jin

Haojie Huang

Lei Li

Affiliations

Soon will be listed here.

Abstract

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)-facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)-mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.

Citing Articles

Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer.

Su W, Wang W, Zhang G, Yang L Clin Epigenetics. 2025; 17(1):48.

PMID: 40083014 PMC: 11907984. DOI: 10.1186/s13148-025-01852-w.

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